bims-traimu 2025-08-03 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–08–03
fifteen papers selected by
Yantong Wan, Southern Medical University

C-Reactive Protein as a Potential Signpost to Trained Immunity.
Trained immunity in the lung.
Heparin-Binding Hemagglutinin-Induced Trained Immunity in Macrophages: Implications for Antimycobacterial Defense.
Potential effects of PFAS exposure on trained immunity: From mechanisms to health risks.
Trained immunity: novel perspectives in diabetes and associated complications.
Immunization with Complete Freund's Adjuvant Reveals Trained Immunity-like Features in A/J Mice.
Immune priming in the insect gut: a dynamic response revealed by ultrastructural and transcriptomic changes.
Shingles vaccination and neuroimmune vulnerability.
Bacterial Infections Shape Cardiac Macrophages' Response to Ischemia.
Vitamin D and lipopolysaccharide jointly induce a distinct epigenetic and transcriptional program in human monocytes.
The RNA-binding protein RRP1 brakes macrophage one-carbon metabolism to suppress autoinflammation.
The Hippo pathway kinase MST1 mediates a feedback loop to maintain NLRP3 inflammasome homeostasis.
Macrophages form dendrite-like pseudopods to enhance bacterial ingestion.
Transcriptomic Profiling Reveals Distinct Immune Dysregulation in Early-Stage Sepsis Patients.
Ferroptosis mediated by the IDO1/Kyn/AhR pathway triggers acute thymic involution in sepsis.

JACC Basic Transl Sci. 2025 Jul;pii: S2452-302X(25)00269-4. [Epub ahead of print]10(7): 101319

C-Reactive Protein as a Potential Signpost to Trained Immunity.

Robin P Choudhury.



Keywords:  hsCRP; inflammatory risk; monocyte; trained immunity; unstable angina

DOI:  https://doi.org/10.1016/j.jacbts.2025.101319
Elife. 2025 Aug 01. pii: e104918. [Epub ahead of print]14

Trained immunity in the lung.

Elina Idiiatullina, Dane Parker.

  Trained immunity represents a recent concept that elucidates the long-term reprogramming of innate immune cells, enabling them to adapt and respond more effectively to subsequent encounters with diverse pathogens. Initially recognized through the Bacillus Calmette-Guérin vaccine, Candida albicans infection, and β-glucan administration, this phenomenon challenges the traditional view that immune memory is exclusive to the adaptive immune system. Trained immunity is characterized by epigenetic and metabolic modifications in innate immune cells that facilitate enhanced responses to infections through mechanisms like chromatin remodeling and altered gene expression. This review focuses on the implications of trained immunity within the lung environment, which is constantly exposed to a plethora of pathogens and environmental irritants. We discuss the roles of various immune cell types, including alveolar macrophages and dendritic cells, in mediating trained immunity and how these adaptations may influence pulmonary insults and disease. Furthermore, we highlight the potential for leveraging trained immunity to enhance vaccine efficacy and develop novel therapeutic strategies for immune-related lung conditions. As research progresses, understanding trained immunity in the lung could pave the way for innovative interventions that improve lung health and resilience against infections.

Keywords:  airway; alveolar macrophage; immunology; infectious disease; inflammation; innate immune memory; lung; microbiology; trained immunity

DOI:  https://doi.org/10.7554/eLife.104918
Biomolecules. 2025 Jul 04. pii: 959. [Epub ahead of print]15(7):

Heparin-Binding Hemagglutinin-Induced Trained Immunity in Macrophages: Implications for Antimycobacterial Defense.

Yongqiang Li, Xiuping Jia, Jinhua Tang, Huilian Qiao, Jiani Zhou, Yueyun Ma.

  Tuberculosis (TB) is a major global health threat, with the current Bacillus Calmette-Guérin (BCG) vaccine having limited efficacy against adult pulmonary disease. Trained immunity (TI) is a form of innate immune memory that enhances antimicrobial defense. It is characterized by the epigenetic and metabolic reprogramming of innate immune cells and holds promise as a promising approach to prevent TB. In this study, we investigated the capacity of heparin-binding hemagglutinin (HBHA), a methylated antigen of Mycobacterium tuberculosis, to induce TI in murine RAW264.7 macrophages, human-derived THP-1 macrophages, and human peripheral blood mononuclear cells (hPBMCs). HBHA-trained macrophages exhibited the enhanced expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) following secondary lipopolysaccharide stimulation. The epigenetic profiling indicated elevated levels of H3K4me1 and H3K4me3 histone marks at cytokine gene loci. Further, metabolic analysis revealed heightened lactate production and the increased expression of glycolytic enzymes. Functionally, HBHA-trained macrophages exhibited improved control of intracellular mycobacteria, as evidenced by a significant reduction in colony-forming units following BCG infection. These findings elucidate that HBHA induces a functional TI phenotype via coordinated epigenetic and metabolic changes, and suggest HBHA may serve as a valuable tool for studying TI and its relevance to host defense against mycobacterial infections, pending further in vivo and clinical validation.

Keywords:  epigenetic reprogram; heparin-binding hemagglutinin; macrophage; trained immunity; tuberculosis

DOI:  https://doi.org/10.3390/biom15070959
Ecotoxicol Environ Saf. 2025 Jul 28. pii: S0147-6513(25)01102-9. [Epub ahead of print]302 118757

Potential effects of PFAS exposure on trained immunity: From mechanisms to health risks.

Jingle Qiu, Xia Huo, Yifeng Dai, Yu Huang, Xijin Xu.

  Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a class of persistent organic pollutants that are widely used in industry and consumption due to their unique chemical properties, but their extreme persistence and bioaccumulation potential pose significant risks to human health. There is growing evidence that PFAS exposure may disrupt trained immunity-a novel form of innate immune memory driven by epigenetic and metabolic reprogramming-thereby enhancing immune responses upon re-exposure to pathogens. While the immunotoxic effects of PFAS have been extensively studied in the context of adaptive immunity, their impact on trained immunity represents a groundbreaking and underexplored area of research. This study reviews recent studies on the effects of PFAS exposure on the innate immune system, evaluating the mechanisms by which PFAS disrupt trained immunity through epigenetic regulation and metabolic reprogramming, and the emerging evidence suggesting potential links between PFAS-induced dysregulation of trained immunity and autoimmune pathogenesis and chronic inflammation. Given the environmental persistence and widespread distribution of PFAS, further mechanistic research is essential to elucidate their immunotoxic effects on human health, which will be critical for developing targeted prevention strategies and informing evidence-based regulatory decisions.

Keywords:  Epigenetic inheritance; Health risk; Metabolic reprogramming; PFAS; Trained immunity

DOI:  https://doi.org/10.1016/j.ecoenv.2025.118757
Front Immunol. 2025 ;16 1613602

Trained immunity: novel perspectives in diabetes and associated complications.

Yukun Liu, Yanqi Lei, Zhuojun Dai, Changfang Luo, Qiming Gong, Yanqun Li, Yong Xu, Wei Huang.

  Recent studies have revealed that the innate immune system possesses the capacity to develop "trained immunity" via metabolic and epigenetic reprogramming, leading to non-specific memory responses distinct from the memory traditionally attributed exclusively to adaptive immunity. Hyperglycemia, acting as an initiating stimulus, drives myeloid progenitor cell proliferation and monocyte-derived macrophage expansion, which leads to a sustained pro-inflammatory phenotype that is closely associated with the pathogenesis of diabetes and its related complications. The paradigm of trained immunity provides a novel perspective on explaining the "metabolic memory" phenomenon in diabetes. Here, we summarize the research progress on trained immunity, diabetes, and related complications to explore novel insights into diabetes prevention and treatment.

Keywords:  diabetes; epigenetics; hyperglycemia; inflammation; metabolism; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2025.1613602
Vaccines (Basel). 2025 Jul 21. pii: 768. [Epub ahead of print]13(7):

Immunization with Complete Freund's Adjuvant Reveals Trained Immunity-like Features in A/J Mice.

Kiruthiga Mone, Shraddha Singh, Fatema Abdullatif, Meghna Sur, Mahima T Rasquinha, Javier Seravalli, Denise K Zinniel, Indranil Mukhopadhyay, Raul G Barletta, Teklab Gebregiworgis, Jay Reddy.

   BACKGROUND/OBJECTIVES: Freund's adjuvants induce different immunomodulatory effects, but their underlying molecular mechanisms are unclear. In this study, we investigated whether the immune-stimulating effects of the complete Freund's adjuvant (CFA) involve the mechanisms of trained immunity (TI).
METHODS: We examined bone marrow cells (BMCs) isolated from CFA-immunized A/J mice to address this question. Incomplete Freund's adjuvant (IFA) and Mycobacterium tuberculosis var. bovis Bacillus Calmette-Guérin (BCG) served as negative and positive controls, respectively. We evaluated cytokine profiles, metabolic, and epigenetic changes.
RESULTS: First, BMCs from all groups except saline showed varied levels of IL-1β, IL-6, and TNF-α. But expression of CCL5 and CXCL10 was significantly elevated only in the CFA and BCG groups. Transcriptionally, significant elevations were noted for TNF-α and IL-1β in the CFA and BCG groups, whereas CXCL10, IL-6, and IL-10 were upregulated in the CFA and BCG groups, respectively. Second, while BMCs from the BCG group expressed the markers of both the M1 and M2 macrophages, no clear trends were noted in the CFA and IFA groups. Third, cell lysates from the CFA group revealed metabolic reprogramming in the BMCs. Specifically, we observed an increased level of lactate, indicative of aerobic glycolysis, which is implicated in TI, and this was also detected in the IFA group. Fourth, epigenetic analysis revealed histone enrichment in the promoter region of TNF-α, in the CFA group, but to a lesser degree than the BCG group. However, no epigenetic changes were observed in the IFA group.
CONCLUSIONS: Our data provide new insights into the mechanisms of Freund's adjuvants and the immunomodulatory effects of CFA could involve the features of TI.

Keywords:  CFA; Freund’s adjuvants; IFA; adjuvants; complete Freund’s adjuvant; epigenetics; immunometabolism; incomplete Freund’s adjuvant; innate immune memory; metabolomics; trained immunity; vaccine adjuvants

DOI:  https://doi.org/10.3390/vaccines13070768
BMC Biol. 2025 Jul 28. 23(1): 227

Immune priming in the insect gut: a dynamic response revealed by ultrastructural and transcriptomic changes.

Moritz Baur, Nora K E Schulz, Lilo Greune, Zoe M Länger, Jürgen Eirich, Iris Finkemeier, Robert Peuß, Petra Dersch, Joachim Kurtz.

   BACKGROUND: Research on forms of memory in innate immune systems has recently gained momentum with the study of trained immunity in vertebrates and immune priming in invertebrates. Immune priming is an evolutionary ancient process that confers protection against previously encountered pathogens. However, despite the existence of immune priming across many invertebrate taxa, evolution and mechanisms of immune priming are still not well understood. Moreover, it is unclear how natural pathogens might elicit immune priming in their hosts.
RESULTS: Here we combine RNA sequencing with transmission electron microscopy to investigate the dynamic processes during priming in the gut of a well-established model for oral immune priming, consisting of the host Tribolium castaneum and its natural pathogen Bacillus thuringiensis tenebrionis (Btt). We show that priming with specific, pathogen-derived virulence-relevant factors induces gut damage in T. castaneum larvae, triggering an early physiological stress response and upregulation of a distinct set of immune genes. This response diminishes over time yet enables the gut to upregulate genes known to interfere with Btt virulence when later exposed to infectious Btt spores.
CONCLUSIONS: Our findings demonstrate that pathogen-derived factors inducing gut damage and stress responses prime gut tissue to provide more efficient protection against infection. These insights deepen our understanding of the mechanisms driving innate immune memory, which likely evolved as an adaptive response to natural pathogens.

Keywords:   Bacillus thuringiensis ; Evolution of immunity; Innate immune memory; Insect; Invertebrate; Pathogen; Virulence

DOI:  https://doi.org/10.1186/s12915-025-02334-4
Trends Neurosci. 2025 Jul 25. pii: S0166-2236(25)00145-6. [Epub ahead of print]

Shingles vaccination and neuroimmune vulnerability.

Xin Huang, Ben J Gu.

  Recent studies report reduced dementia risk following shingles vaccination, suggesting that varicella-zoster virus (VZV) latency contributes to neuroimmune vulnerability. We propose that subclinical VZV reactivation acts as a renewable peripheral immune stressor, amplifying microglial priming in aging brains. Shingles vaccination may suppress this viral reservoir, reducing cumulative inflammatory tone. In this opinion article we contrast this mechanism with trained immunity and highlight how pathogen-specific and systemic effects may converge. Finally, we discuss the role of innate phagocytosis and resolution, suggesting that impaired clearance, rather than activation alone, sustains neuroinflammatory risk. Vaccination may thus modulate innate responsiveness and preserve neuroimmune balance in later life.

Keywords:  Alzheimer’s disease; aging; innate immunity; neurodegeneration; neuroinflammation; virus

DOI:  https://doi.org/10.1016/j.tins.2025.07.003
Circ Res. 2025 Jul 30.

Bacterial Infections Shape Cardiac Macrophages' Response to Ischemia.

Simon Geissen, Alexander Hof, Elvina Santhamma Philip, Elena Wagner, Charlotte Schreiber, Kezia Singgih, Suchitra Narayan, Harshal Nemade, Linus Maximilian Hohendorff, Niklas Arno Roever, Patrik Schelemei, Michelle Holthaus, Adnana Paunel-Görgülü, Martin Mollenhauer, Holger Winkels, Norbert Gerdes, Kat Folz-Donahue, Anna-Lena Schumacher, Christian Kukat, Stephan Baldus, Timofei Zatsepin, Friedrich Felix Hoyer.

   BACKGROUND: Patients with bacterial infections are at increased risk for subsequent cardiovascular events. Whether infections' effects on innate immune cells within the cardiovascular system influence subsequent pathologies remains unclear. Here, we explore cardiac myeloid cells' chronic adaptations to a preceding bacterial insult and implications for subsequent myocardial ischemia.
METHODS: We used various flow cytometry protocols to assess cardiac immune cells, peripheral leukocytes, and hematopoietic stem and progenitor cells in bone marrow and spleen. A genetic fate-mapping model was used to determine cardiac macrophages' origin after bacteremia. Cardiac leukocytes were analyzed using scRNAseq. Nanoparticle-mediated RNA interference was used to target macrophages in vivo.
RESULTS: Cardiac macrophage numbers increased sharply, and numerical changes alongside subset alterations persisted over time. Fate-mapping pointed toward local origin as the primary macrophage source after infection. Profiling macrophage heterogeneity using scRNAseq, we identified 2 previously unknown subpopulations remaining after resolution of infection. While heightened metabolic activity was one subset's primary feature, the other displayed excessive chemotactic properties, which amplified cardiac leukocyte recruitment and inflammation after a subsequent ischemic injury. Targeting cardiac macrophages' surplus inflammatory activity after infection using nanoparticle-enabled, macrophage-directed RNA interference kept disproportionate subsequent ischemic inflammation at bay.
CONCLUSIONS: Bacteremia induces long-lasting changes in the cardiovascular system's innate immune cells' composition. This may amplify myocardial inflammation after a subsequent ischemic injury.

Keywords:  infections; inflammation; macrophages; myeloid cells; myocardial infarction

DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325147
Sci Rep. 2025 Jul 28. 15(1): 27480

Vitamin D and lipopolysaccharide jointly induce a distinct epigenetic and transcriptional program in human monocytes.

Mariusz Jankowski, Emmi Hämäläinen, Mari Taipale, Sami Heikkinen, Carsten Carlberg.

  Pathogen-associated molecular patterns such as lipopolysaccharide (LPS) mimic immune responses triggered by bacterial infections. The hormonally active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], supports innate immunity, but its molecular mechanisms remain incompletely understood. We investigated epigenomic and transcriptomic changes in THP-1 monocytes that were either unprimed or primed for 24 h with 1,25(OH)2D3 or LPS, followed by a second 24-hour stimulation with 1,25(OH)2D3, LPS, or their combination. Epigenome profiling via ATAC-seq revealed that co-stimulation with 1,25(OH)2D3 and LPS induces substantially more chromatin accessibility changes than either treatment alone, with up to 81% of altered regions uniquely responsive to the combination. Motif enrichment analysis highlighted JUN/FOS transcription factors as key regulators of this synergistic response. Transcriptomic analysis via RNA-seq mirrored these findings, though fewer genes than chromatin regions were affected. Notably, under 1,25(OH)2D3-primed conditions, 331 genes exhibited synergistic expression changes upon co-treatment, meaning that their responses significantly deviates from the additive effects of the individual stimulations. This includes 264 genes previously unrecognized as vitamin D targets. Functional annotation revealed that these genes are primarily linked to monocyte and T cell differentiation, in contrast to classical vitamin D targets associated with inflammation. In conclusion, our findings provide mechanistic insight into how vitamin D modulates inflammation through epigenetic and transcriptional reprogramming.

Keywords:  Chromatin accessibility; Immune challenge; Lipopolysaccharide; Responsive genes; Transcriptome; Vitamin D

DOI:  https://doi.org/10.1038/s41598-025-10921-2
Nat Commun. 2025 Jul 25. 16(1): 6880

The RNA-binding protein RRP1 brakes macrophage one-carbon metabolism to suppress autoinflammation.

Yumei Zhou, Mengxuan Li, Ke Jin, Mingyue Wen, Hua Qin, Yue Xu, Chunmei Wang, Xuan Zhang, Xuetao Cao.

RNA-binding proteins (RBP) are important for the initiation and resolution of inflammation, so better understanding of RBP-RNA interactions and their crosstalk with metabolism may provide alternate targets to controlling inflammation. Here we establish global RNA-protein interactome purification (GRPIp) to profile the RBP landscape in inflammatory primary macrophages and identify ribosomal RNA processing 1 (RRP1) as a suppressor of inflammatory innate responses. Mechanistically, RRP1 binds nuclear thymidylate synthetase (Tyms) transcript and decreases TYMS expression post-transcriptionally in inflammatory macrophages, consequently suppressing folate metabolism cycle and inhibiting one-carbon metabolism-driven inflammation. Myeloid-specific RRP1-deficient mice develop severe experimental arthritis with increased pro-inflammatory cytokines and immunologic injury. Meanwhile, in patients with rheumatoid arthritis, RRP1 expression in peripheral blood monocytes negatively correlates with TYMS expression and serum IL-1β levels. Our results thus suggest that RRP1 acts as an anti-inflammatory factor through braking one-carbon metabolism post-transcriptionally, thereby implicating potential strategies for controlling autoinflammation.

DOI: https://doi.org/10.1038/s41467-025-62173-3
Cell Rep. 2025 Jul 26. pii: S2211-1247(25)00847-2. [Epub ahead of print]44(8): 116076

The Hippo pathway kinase MST1 mediates a feedback loop to maintain NLRP3 inflammasome homeostasis.

Xiawei Huang, Jiahui Wang, Yao Liu, Huimin Pan, Kewei Zheng, Bo Liu.

  Inflammasomes play pivotal roles in inflammatory responses. However, their activity must be tightly controlled to prevent overactivation and subsequent inflammatory diseases. Negative feedback loops represent a general mechanism to maintain signaling homeostasis, yet the mechanisms by which inflammasomes employ this process to prevent overactivation remain poorly understood. Here, we identify a negative feedback loop mediated by the Hippo pathway kinase mammalian Ste20-like kinase 1 (MST1) that prevents hyperactivation of the NLRP3 inflammasome. Mechanistically, NLRP3 inflammasome activation induces caspase-1-dependent cleavage of MST1 on its inhibitory linker region, resulting in enhanced kinase activity. The enhanced MST1 phosphorylates the inflammasome adaptor protein ASC at serine 58, disrupting ASC oligomerization and thereby attenuating inflammasome assembly. Notably, staurosporine (STS), a chemical inducer of MST1 cleavage, mitigates inflammation and tissue damage in a lipopolysaccharide (LPS)-induced sepsis mouse model. These findings reveal a negative feedback mechanism for maintaining inflammatory homeostasis and highlight MST1 cleavage as a potential therapeutic target for controlling inflammation.

Keywords:  ASC; CP: Immunology; CP: Molecular biology; Hippo pathway; MST1/2; NLRP3; caspase-1; endoproteolytic cleavage; feedback loop; inflammasome; phosphorylation

DOI:  https://doi.org/10.1016/j.celrep.2025.116076
EMBO J. 2025 Jul 28.

Macrophages form dendrite-like pseudopods to enhance bacterial ingestion.

Changyuan Fan, Xinyi Huang, Jie Mei, Xuemeng Shi, Hao Zhang, Cong Liang, Shuzhi Cui, Yifan Xing, Biao Cao, Wei Liu, Huisheng Liu, Bo Liu, Wakam Chang, Mengle Shao, Gong-Hong Wei, Yan-Jun Liu, Zheng-Jun Chen, Zhaoyu Lin, Tao Xu, Yaming Jiu.

  Macrophages are critical innate immune cells that exhibit remarkable adaptability during pathogen infections. However, the relationship between their morphological plasticity and physiological functions remains largely elusive. Here, we discovered an unprecedented paradigm of macrophage adaptation within a few hours upon severe Gram-negative bacterial infections, characterized by the formation of dendrite-like pseudopods (DLPs). Using in vitro, microfluidic, and in vivo infection models, we demonstrate that these pseudopods enhance bacterial uptake by expanding the macrophage searching radius, thereby bolstering host defense. Mechanistically, Toll-like receptor 4 (TLR4) activation by Gram-negative bacterial lipopolysaccharide (LPS) upregulates the expression of macrophage-specific RhoGEF and ARHGEF3 in an NF-κB-dependent manner. ARHGEF3 localizes to dendrite-like pseudopods and enhances RhoA activity. Consequently, periodic cycles of actin assembly and disassembly propel the elongation of pseudopods, whereas vimentin intermediate filaments stabilize them. Importantly, infusion of DLP-equipped macrophages into Salmonella-infected mice reduced bacterial burden and infection severity. Together, our findings underscore how the dynamic response of macrophages to massive infections can augment immune defense against pathogenic bacteria.

Keywords:  Actin Filaments; Dendrite-like Pseudopods; Macrophage; Pathogen Ingestion; Vimentin Intermediate Filaments

DOI:  https://doi.org/10.1038/s44318-025-00515-z
Int J Mol Sci. 2025 Jul 11. pii: 6647. [Epub ahead of print]26(14):

Transcriptomic Profiling Reveals Distinct Immune Dysregulation in Early-Stage Sepsis Patients.

Safa Taha, Khaled Bindayna, Muna Aljishi, Ameera Sultan, Nourah Almansour.

  Sepsis is a life-threatening condition characterized by dysregulated immune responses to infection. To elucidate early transcriptional changes in sepsis, we conducted a case-control study profiling gene expression in whole blood from 20 early-stage sepsis patients and 9 healthy controls. Using Affymetrix Clariom D Human Arrays and robust preprocessing, we identified differentially expressed genes (DEGs) using standard bioinformatic pipelines. A total of 344 genes were significantly upregulated, while 9703 were significantly downregulated in sepsis patients (|log2FC| > 1, adjusted p < 0.05). Pathway enrichment and Gene Ontology analysis revealed activation of innate immune pathways, neutrophil degranulation, and cytokine signaling, alongside suppression of lymphocyte differentiation and antigen presentation. These results suggest a shift toward an innately driven inflammatory state in early sepsis. Our findings provide transcriptomic insights that may support the development of early diagnostic biomarkers and therapeutic targets.

Keywords:  differential gene expression; early diagnosis; innate immunity; microarray; sepsis; transcriptomics

DOI:  https://doi.org/10.3390/ijms26146647
Cell Death Dis. 2025 Jul 25. 16(1): 562

Ferroptosis mediated by the IDO1/Kyn/AhR pathway triggers acute thymic involution in sepsis.

Zimei Cheng, Kexin Wang, Yixue Wang, Tingyan Liu, Jingjing Li, Yaodong Wang, Weiming Chen, Reyihangu Awuti, Hetian Zhou, Wenjia Tong, Zhenhao Yu, Yao Wang, Guoyun Su, Weiguo Yang, Yufeng Zhou, Guoping Lu, Caiyan Zhang.

Acute thymic involution (ATI) is frequently observed during sepsis, however the underlying mechanisms remain poorly understood. This study demonstrates that ferroptosis plays a crucial role in sepsis-associated ATI. We found that pediatric sepsis patients showed significantly elevated kynurenine (Kyn)/tryptophan (Trp) ratios, indicating increased indoleamine 2,3-dioxygenase 1 (IDO1) activity, along with higher Kyn levels compared to controls. Moreover, Kyn levels were negatively correlated with thymus-to-thorax ratio. Further mechanistic analysis revealed that the enhanced expression of IDO1, induced by inflammatory signals, drives the accumulation of Kyn and subsequent activation of the aryl hydrocarbon receptor (AhR), triggering lipid oxidation-related gene transcription and ferroptosis in thymocytes during sepsis. Treatment with 1-methyltryptophan (IDO1 inhibitor) effectively restore thymic function and improve survival in septic mice. Our findings reveal a novel role for the IDO1/Kyn/AhR pathway in ferroptosis, suggesting that targeting this pathway may offer a promising therapeutic strategy for sepsis. Created with BioRender ( https://app.biorender.com/ ).

DOI: https://doi.org/10.1038/s41419-025-07882-9